A biomaterial can be defined as any matter, surface, or construct that interacts with biological systems, such as e.g. cells, tissue, organs and blood. Especially, when biomaterials are used in in vivo applications, for example as implants, these materials need to fulfil to a list of demands with respect to e.g. non-toxicity, biocompatibility, biodegradability, mechanical performance, processability, synthetic accessibility and production control. In particular demanding in vivo applications, the materials may be required to degrade at a controlled (slow) rate, while the materials should still perform mechanically.
Biomaterials can be prepared from natural or synthetic resources. Biomaterials from natural resources (polyamide fibres such as silk or collagen and polysaccharides such as chitosan and cellulose) are often difficult to control in terms of their exact composition and in terms of their properties and processing.
Biomaterials from synthetic resources (polyesters such as poly-ε-caprolactone, polyglycolides, polylactides and copolymers of these polyesters) have frequently been used for implants and for scaffolds for tissue engineering. These polymers, however, are limited in their mechanical behaviour, as they are hard, brittle and virtually not elastic. Upon cross-linking, the mechanical properties of these polymers may become better, but after cross-linking these materials can no longer be processed.
Several of these polymers are (semi)crystalline, for example poly-ε-caprolactone is a semi-crystalline material (i.e. they melt at about 60°-65° C.). This is disadvantageous because the properties of semi-crystalline materials may change in time due to prolonged (re)crystallization processes taking place in the material, e.g. while being used at about 37° C. as implant. Finally, synthetic polyesters usually degrade relatively fast in vivo.

One class of synthetic biomaterials are polyester urethane ureas (PEUUs). These biomaterials are usually described as thermoplastic elastomers (TPEs), as they contain phase separated soft blocks A (i.e. the polyester main chain) and hard blocks B (the aggregated hydrogen bonded urea and/or urethane segments). In a typical synthesis process (cf. Scheme A) of PEUUs, a prepolymer polyester diol (used for the soft block) is reacted in a first step with a diisocyanate thereby forming a prepolymer with isocyanate functions. The latter is chain extended with a diamine in a second step thereby forming a polyester with urethane and bisurea hydrogen bonding units in its main chain (the hard blocks). PEUUs formed by such a process are, however, not strictly segmented polymers, but statistically segmented polymers. They contain hard blocks and soft blocks of various nature and degree of polymerisation, so that these PEUUs have main chain structures with a limited molecular definition, because the first step gives a statistical mixture of products, so that in the second step not two, but actually a range of species react with one another. As a result, the prepared material will be a segmented material that can be represented by the formula [(A)p(B)q]n, as every soft block A and every hard block B in one polymer chain can be of a different nature (p and q can be 0, 1, 2, etc. throughout the polymer chain; n represents the number of repeats of the (A)p(B)q segments). Accordingly, the material will be composed of a wide variety of macromolecular architectures. Reference is further made to Comparative Example 42 of this patent application.
Wagner et al. (J. Biomed. Mater. A, 603-614, 2004; incorporated by reference) discloses a polycaprolactone urethane urea which is prepared according to the process described above. This polymer does not have monodisperse hard blocks and has a limited molecular definition. It is a segmented [(A)p(B)q]n material.
Hong et al. (Biomaterials 31, 4249-4258, 2010) and Ma et al. Biomacromolecules 12, 3265-3274, 2011; both incorporated by reference), disclose other polymers which are prepared by the same synthetic approach. A (mixture of a) polycaprolactone diol and/or a polycarbonate diol are reacted with a diisocyanate, after which the obtained prepolymer in situ (i.e. no purification) is chain extended with a diamine. Again, the final polymer does not have monodispersed hard blocks and has a limited molecular definition. Moreover, the highly toxic fluorinated solvent hexafluoroisopropanol (HFIP) is used as processing solvent for the prepared materials, but e.g. electrospinning data are not shown. Materials with melting transitions as high as 40° C. have been reported, and all polycaprolactone based materials display accelerated degradation.
US 2008/009830, incorporated by reference, discloses a biodegradable elastomeric patch comprising a polymer composition comprising a PEUU, a polyether ester urethane urea (PEEUU) or a combination thereof. According to [0047] and [0048], these polymers are preferably prepared by the process disclosed above.
US 2008/109070, incorporated by reference, discloses a biodegradable elastomeric scaffold comprising a linear segmented PEUU and PEEUU. According to [0048], and [0067], these polymers are preferably prepared by the process disclosed above.
WO 2011/150328, incorporated by reference, discloses an implantable matrix comprising a biodegradable elastomeric polymer, preferably a PEUU, a PEEUU, a polyester carbonate urethane urea (PECUU) or a polycarbonate urethane urea (PCUU). According to page 6, line 18—page 7, line 2 and page 10, lines 4-23, the PEUU and the PEEUU may be prepared by the process disclosed above.
Segmented TPEs with monodisperse hard blocks and non-biodegradable soft blocks are known. For example, non-biodegradable polysiloxanes are disclosed in Yilgor et al., Polymer 41, 849-857, 2000. Polyether TPEs are disclosed in Versteegen et al., Macromolecules 38, 3176-3184, 2005; Gaymans et al., Progress in Polymer Science 36, 713-748, 2011; Sijbrandi et al., Macromolecules 45, 3948-3961, 2012; and Sijbrandi et al., Polymer 53, 4033-4044, 2012, and WO 2011/087650 (all incorporated by reference), and these non-biodegradable polyethers are in most cases incorporated into the TPE products by using high polymerisation (polycondensation) or processing temperatures (>190° C.). Such higher temperatures are not ideally suited to be used with e.g. biodegradable polyesters, as these polymers may degrade at these high temperatures.
US 2005/234215, incorporated by reference, discloses copolymers comprising amide segments, said copolymers having a glass transition temperature Tg lower than 0° C.
US 2006/217500, incorporated by reference, discloses copolymers comprising amide segments, said copolymers having a glass transition temperature Tg higher than 120° C.
In some cases, segmented TPEs with monodisperse crystallisable hard blocks have been reported, where the soft block is a polyester.
Wisse et al., Macromolecules 39, 7425-7432, 2006, Wisse et al., Biomacromolecules 6, 3385-3395, 2006; and EP 1985319 (all incorporated by reference) disclose bisurea polycaprolactone (PCL) polymers, where the polycaprolactone soft blocks are prone to crystallize. Materials displaying melting transitions of the soft block as high as 42° C. are reported, and these are therefore not considered as soft blocks anymore.
Sontjens et al., Macromolecules 41, 5703-5708, 2008, incorporated by reference, discloses amorphous propylene-adipate TPEs with (aromatic, non-aliphatic) UPy groups (Upy means 2-ureido-[1H]-pyrimidin-4-one) in the main chain. The HDI (n-hexylene diisocyanate) based material shows a hard block melt at a relatively low temperature (78° C.), and slow hard block crystallization as none is observed in DSC experiments. No melting point is observed for the material with the (isomeric mixture) isophorone diisocyanate (IPDI) based hard block. The materials show rather low Young's moduli (ca. 1-8 MPa) and tensile strengths (below 3 MPa).
WO 2014/007631, incorporated by reference, discloses implants comprising a matrix material, wherein the matrix material comprises polyesters with UPy or urea groups in their structure. For the urea polyester in vivo data beyond 7 days are not reported.
U.S. Pat. No. 4,851,567, incorporated by reference, discloses in Example 3 a cast polymerisation process wherein a polyester amine (prepared from a NCO prepolymer made from 1 molar equivalent of a polyester based on adipic acid and ethylene glycol and 2 molar equivalents of 2,4-diisocyanate toluene (TDI) followed by hydrolysis of the NCO prepolymer) is reacted with naphthalene-1,5-diisocyanate. The reaction of prepolyester diol and TDI is a reaction that produces a range of prepolymer diisocyanate species (statistical process). Furthermore, a too large drop is observed when comparing the OH-number of the prepolyester alcohol and the NH-number of the prepolyester amine indicating that side reactions have taken place. Accordingly, materials with a limited molecular definition wee prepared.
U.S. Pat. No. 4,569,982, incorporated by reference, discloses in Example 3 a polymerisation process wherein a polyester amine (prepared from a NCO prepolymer made from a polyester based on adipic acid, ethylene glycol and butane-1,4-diol) and 2,4-diisocyanate toluene followed by hydrolysis of the NCO prepolymer) is reacted with 2,4-diisocyanate toluene.
U.S. Pat. No. 4,532,317, incorporated by reference, discloses in Example 8 the preparation of a polyester amine by hydrolysis of a NCO prepolymer made from a polyester based on adipic acid, ethylene glycol and butane-1,4-diol and 2,4-diisocyanate toluene. Examples 39 and 40 disclose a polymerisation process of similar polyester amines, butane-1,4-diol and 4,4′-diisocyanate diphenylmethane (MDI).
There is, however, still a need in the art for biodegradable materials that have improved durable mechanical properties (elastic properties, toughness) which can be easily moulded and/or easily processed from either the melt or from solution.
The objective of the present invention is to provide such biodegradable materials.